Journal ArticleDOI
Diltiazem Enhances the Apoptotic Effects of Proteasome Inhibitors to Induce Prostate Cancer Cell Death
Ismail Kaddour-Djebbar,Vivek Choudhary,Vivek Choudhary,Vijayabaskar Lakshmikanthan,Vijayabaskar Lakshmikanthan,Vijayabaskar Lakshmikanthan,Robert Shirley,Robert Shirley,Manal El Gaish,Mohamed Al-Shabrawey,Belal Al-Husein,Belal Al-Husein,Roger Zhong,Michael Davis,Zheng Dong,Wendy B. Bollag,M. Vijay Kumar,M. Vijay Kumar,M. Vijay Kumar +18 more
TLDR
The results demonstrate a potential therapeutic advantage of combining a frequently used calcium channel blocker with proteasome inhibitors in the treatment of prostate cancer by inducing apoptosis in a dose-dependent and synergistic manner.Abstract:
Diltiazem is a calcium channel blocker used to treat cardiovascular ailments. In addition, reports suggest that diltiazem induces cell death, which could make it a drug of choice for the treatment of cancer associated with hypertension. The goal of this research was to determine whether diltiazem is capable of inducing apoptosis in prostate cancer cells, either alone or in combination with the proteasome inhibitors, lactacystin and bortezomib (Velcade). Bortezomib is approved for the treatment of multiple myeloma; unfortunately, it has side effects that limit its utility. Presumably these side effects could be decreased by reducing its dose in combination with another drug. We have previously shown that lactacystin induces apoptosis in LNCaP cells; here, we show that this effect was enhanced by diltiazem. Furthermore, in proteasome inhibitor-resistant DU145 cells, diltiazem alone did not induce apoptosis but decreased cytosolic calcium levels and induced mitochondrial fission; likewise, lactacystin did not induce apoptosis but up-regulated the proapoptotic protein Bik. However, increasing concentrations of diltiazem in combination with lactacystin or bortezomib induced apoptosis in a dose-dependent and synergistic manner. The combination of diltiazem and lactacystin also up-regulated the levels of Bik and released Bak from Bcl-xL, indicating the involvement of the Bcl2 family pathway in this apoptosis. In addition, the drug combination up-regulated GRP78, suggesting also the involvement of endoplasmic reticulum stress in the apoptotic response. Thus, our results demonstrate a potential therapeutic advantage of combining a frequently used calcium channel blocker with proteasome inhibitors in the treatment of prostate cancer.read more
Citations
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Journal ArticleDOI
NFAT as cancer target: mission possible?
TL;DR: The mechanisms that drive the activation of various NFAT isoforms in cancer are discussed and the potential of NFAT as a valid target for cancer prevention and therapy is analyzed.
Book ChapterDOI
Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges
TL;DR: A growing body of evidence suggests that a range of existing and novel Na+, K+, Ca2+ and Cl- channel inhibitors may be effective for suppressing cancer cell proliferation, migration and invasion, as well as enhancing apoptosis, leading to suppression of tumour growth and metastasis, either alone or in combination with standard-of-care therapies.
Journal ArticleDOI
Anticancer Effects of Antihypertensive L-Type Calcium Channel Blockers on Chemoresistant Lung Cancer Cells via Autophagy and Apoptosis.
TL;DR: Verapamil combined with DOC or VCR induces chemoresistant lung cancer cells to death through autophagy burst and apoptosis more strongly than Diltiazem and Nifedipine; mechanism of caspase-independent cell death also contributes to Verapamils/chemotherapy-induced anticancer effects.
Journal ArticleDOI
Calcium channel blockers and prostate cancer
TL;DR: There is evidence that calcium channel blockers induce cytotoxicity in androgen receptor positive cell lines and may offer an innovative strategy for the treatment of castration-resistant prostate cancer.
Journal ArticleDOI
No evidence for increased prostate cancer risk among calcium channel blockers user
TL;DR: There was a positive association between CCB use and prostate cancer risk in case–control studies but an inverse association in prospectivecohort studies; however, in the stratified analyses, the results were substantially affected by study design.
References
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